Monday’s announcement for the Nobel Prize in physiology or medicine should have been a happy occasion for my lab. On the one hand, it was given for early discoveries in the field of innate immunity – my field! On the other hand, it was given to a scientist that many* feel is undeserving of the honor, while at the same time sullying the legacy of my scientific great-grandfather.

Let me explain.The Context

In the late 1980’s, immunologists were riding high. Much of the experimental attention in previous decades had focused on T-cells and B-cells, the drivers of “adaptive immunity,” and it seemed as if they had almost everything figured out. B-cells were known to make antibodies that could be released into the blood and fight infections all over the body. The activity of antibodies was discovered by German scientists over 100 years earlier (which is maybe why it is known by the archaic-sounding term “humoral” immunity), but it was only in the second half of the 20th century that scientists started uncovering the mechanisms behind antibody function. At the same time, the closely related T-cell was yielding its secrets to ingenious experiments. T-cells are behind “cell-mediated” immunity. Where antibodies can be released into blood and carry out their activities independent of the cells that make them, T-cells kill infected cells by sidling up next to them and giving them a kiss of death.

T-cells and B-cells are called “adaptive,” because the receptors that they use to recognize pathogens are generated at random by cutting and rearranging pieces of genes and stitching them together in a random order. These receptors are therefore capable of recognizing functionally any molecule. In addition, both types of cells can learn during the course of an infection and remember what they learned, so that future infections with the same agent can be dealt with more quickly. By the late 80’s immunologists thought they had a handle on how all of this worked.Charlie Janeway’s Insight
In 1989, as an introduction to the Cold Spring Harbor Symposium on Immune Recognition, Charles Janeway wrote1:

I believe it is safe to state that our understanding of immunological recognition is approaching some sort of asymptote, where future experiments are obvious, technically difficult to perform, and aim to achieve ever higher degrees of precision rather than revolutionary changes in our understanding.

But Charlie was just being coy with this paragraph. The title of this paper is “Approaching the Asymptote?” And it turns out that question mark is vital to his thesis. Later on in the same paper, Janeway wrote:

I believe that ideas, especially good ideas, can so satisfy our desire to explain what we’re studying that they can inhibit our ability to explore and to understand.

In the preceding decades, a group of scientists had been quietly plugging away at another, less flashy aspect of immunity. The receptors that controlled recognition for this type of immunity seemed boring next to their T-cell and B-cell counterparts; they are present from birth, don’t rearrange genes and recognized a small, fixed set of microbial products. These so-called “innate” immune receptors were made by cells that are present at all times in tissues (rather than being recruited there during an infection like B-cells and T-cells) and it was widely believed that these cells’ only job was to hold an infection at bay while waiting for B-cells and T-cells to show up and dominate the show.

But T-cell and B-cell immunologists had what Janeway called their “dirty little secret.” T-cells and B-cells could recognize any protein, but they can’t mount an immune response on their own. Injection of purified proteins doesn’t lead to immunity, or activation of T-cells and B-cells. Janeway:

In order to obtain readily detectable responses to these [proteins], they must be incorporated into a remarkable mixture termed complete Freund’s adjuvant, heavily laced with killed Mycobacteriam tuberculosis organisms or precipitated in alum and mixed with dead Bordetella pertussis organisms

These special additions are called “adjuvants,” and they are absolutely necessary to get immune activation with pure proteins.

Why do we need to use adjuvants? To be quite honest, the answer is not known.

But Janeway had a theory. In the preceding years, scientists had discovered that in addition to the signal T-cells and B-cells received through their main receptors, they required a second signal, or “co-stimulation.” Other researchers had independently shown that certain microbial products like LPS, a component of bacterial cell walls, had strong adjuvent activities. Janeway’s insight was that the 2nd signal for T-cell and B-cell activation was linked to recognition of particular molecular patterns associated with infection.

I contend that the immune system has evolved specificalty to recognize and respond to infectious microorganisms, and that this involves recognition not only of specific [proteins], but also of certain characteristics or patterns common on infectious agents but absent from the host[…] By ignoring the importance of this microbial component of immunological recognition, I contend that we have collectively ignored a critical feature of self/nonself discrimination, the requirement for a microbially induced second signal[…] Indeed, I believe that if we fail to incorporate such ideas into our thinking, we shall fail to understand immune recognition at its most fundamental level, that is, the discrimination of self from nonself, and in the defense of the host against infection.

The Evidence

It would take almost 10 years to validate Janeway’s prediction. In 1996, Jules Hoffman and colleagues published the paper2 for which Hoffman received the Nobel, showing that a receptor called “Toll” was essential for fruit flies to mount an immune response against fungus. At the same time, Janeway and his post-doc, Ruslan Medzhitov, were investigating a protein they were calling “human Toll” (now known as Toll-like receptor 4 or TLR4), and had shown that when cells expressed a version of the receptor that was always active, it turned on a pathway known to be important in immunity. Galvanized by Hoffman’s discovery3, Medzhitov and Janeway published a paper4 in 1997 showing that this human toll also turned on proteins known to be involved in co-stimulating T-cells and B-cells.

Medzhitov and Janeway didn’t know the natural activator of human Toll, but based on their evidence and the known immune function of the fly toll, they hypothesized that it was involved in the innate recognition of microbial products, and would lead to co-stimulation for the adaptive immune system. After that, the discoveries came fast. In September of 1998, Paul Godowsky and colleagues showed5 that TLR2 responded directly to microbial products, and in December of the same year, Bruce Beutler published his Nobel paper6, showing that TLR4 was the receptor for LPS.

The Controversy

The 2011 Nobel Prize for physiology or medicine was awarded to Ralph Steinman, Bruce Beutler and Jules Hoffmann. According to the press release:

Bruce Beutler and Jules Hoffmann discovered receptor proteins that can recognize such microorganisms and activate innate immunity, the first step in the body’s immune response.

No one denies that Jules Hoffman’s discovery of the immune function of Toll in flies is significant, but Beutler’s contribution is a bit more dubious. Before Beutler’s paper, Medzhitov and Janeway had shown that TLR4 could activate innate immune signals that led to the activation of co-stimulation, and Godowsky had shown that a different receptor, TLR2, could recognize microbial products. Though Beutler’s paper was the first to actually knock out the gene for one of these receptors and show a loss of function in the mouse, the conceptual groundwork for its importance in the immune response had already been laid.

This Nobel was awarded for

the mechanisms triggering the activation of innate immunity and mediating the communication between innate and adaptive immunity.

This was the paradigm suggested by Janeway in 1989 and validated by discoveries in the late 90’s. Beutler just found a receptor that bound to LPS. Janeway and Medzhitov were the first to establish the link to adaptive immunity, and Medzhitov and others (not Beutler) followed his initial discovery by showing the direct links to T-cell activation, B-cell activation and establishing adaptive immune responses. In fact, Beutler has recently been disavowing the idea that pattern recognition is important for adaptive responses7.

I should note here that I’m not exactly an unbiased source (though I think the publication record speaks for itself). My boss was a post-doc in Medzhitov’s lab, putting him (and me) in Janeway’s direct lineage. And there’s no love lost between Medzhitov and Beutler. For the past decade, Beutler has been publishing review articles playing up his own contribution and down-playing that of Janeway. And the feud isn’t restricted to the peer reviewed journals. The latest sortie in this rivalry occurred earlier this year, after Medzhitov gave a presentation to an audience of innate immunologists (including Beutler). At the end of his talk, Medzhitov announced that he wouldn’t take questions, but wanted to comment on the fact that “someone” had changed the wikipedia entry on Charlie Janeway to read:

Janeway and coworkers did not actually demonstrate the existence of receptors for LPS or any other PAMPs. However, receptors for specific molecules made by microbes were eventually identified by other workers, notably [[Bruce Beutler]] , who discovered the LPS receptor[…]

He didn’t name names, but said “there’s only one person that would do this, and we all know who.” And I don’t think he was referring to Sarah Palin.

Janeway couldn’t be awarded the Nobel, since they aren’t granted posthumously. One could argue that Medzhitov shouldn’t get it either, since he wasn’t the principal investigator when his TLR paper was published. But his initial discovery, and his later work as an independent investigator firmly established the role of pattern recognition in the activation of adaptive immunity. In addition, Ralph Steinman (one of the other winners this year), was not the principal investigator on his key paper.

But regardless of the arguments for or against Medzhitov, giving the reward to Beutler, especially in light of the efforts he took to discredit Janeway and his contribution is a bit of a slap in the face. When the history books are written about this era in immunology, I wonder if this Nobel will help Beutler in sweeping Janeway under the rug.

Comments

Janeway couldn’t be awarded the Nobel, since they aren’t granted posthumously

Ironically Ralph Steinman did win this prize posthumously because the committee was unaware that he died of pancreatic cancer 3 days before the prize was announced. Stienman survived for more than 4 years after being diagnosed which is an unusually long time for pancreatic cancer.

It’s disingenuous to describe Bruce Beutler’s contribution as “Beutler just found a receptor that bound to LPS.” Beutler has been publishing research on LPS since 1985. Beutler and his group were the first to show experimentally that TLR4 was required for a response to LPS. That is essentially the Nobel right there. I doubt any serious immunologist would belittle Janeway’s contribution. But to my knowledge neither Janeway nor Medzhitov provided the experimental linkage between LPS and TLR4. Unfortunate as it may seem it is hypothesis testing that wins prizes not proposing an hypothesis. That Beutler’s work may have built on that of others is nothing new to science, it’s the foundation; we see further because of the work of others.

The argument that a change in a Wikipedia entry has somehow impacted the scientific history of TLR research is also a bit rich. The actual science is in the published papers. I doubt very much if the Nobel Committee is swayed by the veracity of Wikipedia entries.

Disclosure: I am an Associate Professor at Scripps Research Institute and have co-authored one publication with Bruce Beutler. My comments here are my own and do not represent those of any other individual or any institution.

One of my mentor once told me that adaptative immunity is pretty important, but nobody lives without innate immnunity. Just look the huge number of organism on history of evolution that have managed to live only with innate immunity. Furthermore patients with a defective adaptative (b type) immunity lives if they regularly receive a infusion of antibody mixture (pool)

@ Mike – I had a line written that I see I cut out saying something like “I’m sure Beutler and his collegues would disagree.” I don’t deny I’m biased based on the folks I’m affiliated with (and in fairness I was in elementary and middle school when this research was being published). I really appreciate you stating your potential bias as well.

Beutler and his group were the first to show experimentally that TLR4 was required for a response to LPS. That is essentially the Nobel right there.

I disagree. That TLR4 binds LPS doesn’t seem to be the reason for the nobel. There are lots of receptors, and lots of ligands. Even in innate immunity there was already MBL and other innate immune receptors long before Polterac et. al. It seems to me that the revolutionary bit about TLRs and pattern recognition is the control that innate immune cells exert on adaptive immunity, the requirement for co-stimulation and the link to self/non-self discrimination. Even the Nobel announcement lists the contribution as “the mechanisms triggering the activation of innate immunity and mediating the communication between innate and adaptive immunity.”

The argument that a change in a Wikipedia entry has somehow impacted the scientific history of TLR research is also a bit rich. The actual science is in the published papers. I doubt very much if the Nobel Committee is swayed by the veracity of Wikipedia entries.

It was not my intention to imply that the wikipedia change had anything to do with the Nobel decision. I agree with you that that would be absurd.

@ Ed – As I replied via twitter, the folks that I know that feel this way are entirely folks that are directly connected to Janeway and Medzhitov. I actually thought of you when I wrote that line, and meant to change it, but that edit fell by the way side at some point. Now that Carl quoted me, I can’t exactly change it :-/

@ Rafael – True, but these days no organisms that evolved with adaptive immunity can live without it.

I am an immunologist who was a graduate student when these seminal findings were published. I am completely unbiased and my work deals primarily with the adaptive immune system. I do not know either of them personally. But I still have to say that I was shocked to hear that Medzhitov was not awarded the prize but Beutler was. So Kevin, I agree with you completely – again as a bystander observer to all the politics and my surprise being based just upon the science. Really quite sad.

I’m another interested observer who has not trained in the labs of the main players (I used to work on pathogenic bacteria), but I have followed the field closely.

The prizes for dendritic cells and PAMPs should have been separate, and (irrespective of Beutler’s contribution) Medzhitov absolutely should have shared the prize.

With respect to the notion that data, not ideas, are important for Nobel prizes, that’s just nonsense. Examples include Delbruck (fluctuation analysis), Burnett (clonal selection), Watson/Crick (model of DNA structure), and many others. And it’s not as though Janeway’s experimental work (and ideas) didn’t provide many of the major signposts followed by Beutler and others. They obviously did.

It is a crying shame that Janeway and Don Wiley did not live long enough to receive the Nobel Prizes that they so obviously and richly deserved; Medzhitov and Pam Bjorkman, the first authors on the key papers, really should be honored for their contributions and those of their advisors. Beutler’s work has been good and informative, but let’s get real: it has not been transformative in the way that the work of the others mentioned here has been, and several other scientists mentioned and unmentioned in this thread have made contributions at least as important at that of Beutler.

To say nothing of the key role of PAMPs in plant immune responses to pathogens, which are, as usual, totally ignored by way too many people in the mainstream immunology community…

@Ex-microbiologist (wouldn’t it be nice to have more disclosure than anonymity)

“With respect to the notion that data, not ideas, are important for Nobel prizes, that’s just nonsense. Examples include Delbruck (fluctuation analysis), Burnett (clonal selection), Watson/Crick (model of DNA structure), and many others.”

It’s an odd argument that the Nobel Prize is awarded for an idea. In science, as anywhere else, ideas are a dime a dozen. If ideas received Nobels we would all have multiple medals and the Nobel would be less significant than published papers. Let’s consider a couple of the examples given. Watson and Crick (and Wilkins) did not receive the Nobel for the model of DNA structure. But even if Watson and Crick did receive their awards for their model was this simply an idea? I encourage those not familiar with the work to read their Nature paper (Nature. 1953. 171:737-8). The model only came about through an understanding of what the x-ray data meant (including Crick’s knowledge to argue that DNA molecules possess perpendicular dyads) and the insight of base pairing due in no small part to Watson’s understanding of which chemical form of the bases were correct. The model was no simple idea.

Frank Macfarlane Burnet (and Peter Medawar) was awarded the Nobel in 1960 “for discovery of acquired immunological tolerance” not clonal selection which came later. While Burnet himself as stated that his contributions to immune tolerance were only theoretical, and were supported experimentally by the work of Medawar. But was Burnet’s work simply ideas? Those who believe so might find it instructive to read Burnet, F. M. and Fenner, F. (1949): Production of Antibodies, 2nd Edition, Macmillan, Melbourne.

Finally it instructive to again revisit why Beutler has received the Nobel for his work. As Medzhitov himself stated in “Approaching the Asymptote: 20 Years Later”. Immunity 30: 766–775, 2009. “Positional cloning of the lps locus by Bruce Beutler and colleagues (Poltorak et al., Science, 282:2085–2088, 1998.) demonstrated that TLR4 was required for LPS responsiveness, thus providing the first genetic evidence for TLR4 function in microbial recognition.” This was the first clear evidence of a specific bacterial product (LPS) requiring a specific TLR (TLR4) to mediate its effects in the whole animal, not an artificial cell system.

@ Mike – There’s quite a lot of debate in the blogosphere about the use of anonymity and pseudonymity, but I’d rather that fight didn’t spread here. I very much appreciate that you’ve used your real name, but let’s not quip at people for their choices on that matter. That said, you went on to address his argument as well, so let’s get to that.

It’s an odd argument that the Nobel Prize is awarded for an idea. In science, as anywhere else, ideas are a dime a dozen. If ideas received Nobels we would all have multiple medals and the Nobel would be less significant than published papers.

This is both true and not true. Watson and Crick had a brilliant insight that was only suggested by the data they had, and others formally proved it. Had their insight been proven false, I don’t think the physical shape of the molecule would have been as important.

Ideas are a dime a dozen, but correct ideas are rare. Janeway’s insight was remarkable in that it synthesized a great deal of what was known at the time, and put it together into a model that made predictions (later validated) that changed the way people thought about innate immunity.

Finally it instructive to again revisit why Beutler has received the Nobel for his work[…] This was the first clear evidence of a specific bacterial product (LPS) requiring a specific TLR (TLR4) to mediate its effects in the whole animal, not an artificial cell system.

Right, but the Nobel wasn’t given for TLRs because TLRs are receptors for microbial products. TLRs have only become so important because of the recognition of their role (and the role of other PRRs) in activation of the adaptive immune response. Again, other innate immune receptors had been described even before the CSHL meeting in 1989. The key insight – that pattern recognition would control the adaptive immune system – was Janeway’s, and Beutler’s work did not actually address this fact.

This Nobel was premature, and completely disregards the more profound issue of the role of endogenous molecules, i.e. danger signals, in the initiation or direction of adaptive immunity. It must be the case that TLRs evolved to recognize endogenous molecules and that these receptors (TLRs) we co-opted by pathogens for their own purposes.

I have to admit that I am a bit shocked that a PhD student in innate immunity isn’t able (or willing) to present the data in the literature correctly, and I can only assume that your “scientific great grandfather” would have kicked your butt for it, if he were still around.

You state:
“….but Beutler’s contribution is a bit more dubious. ….Though Beutler’s paper was the first to actually knock out the gene for one of these receptors and show a loss of function in the mouse,…”

Beutler did no such thing. In the 1998 paper cited in the Nobel announcement (Poltorak et al, Science), Beutler and colleagues identified the “LPS” locus in two mouse strains through positional cloning. The mutations in these two mouse strain occurred spontaneously, rendering these mice resistant to quite substantial concentrations of LPS, while at the same time making them exquisitely sensitive to infections with gram-negative (LPS producing) bacteria. These mice had been described a long time before, but obviously nobody knew the genetic defect causing this behavior. The mutation responsible in both mouse strains turned out to be in the TLR4 gene.

Positional cloning was, especially in those days, a hugely labor intensive and time-consuming effort, taking at least two to three years, and possibly quite a few more. So it is safe to assume that Beutler’s lab had initiated this project well before the 1996 Hofmann publication and certainly before the 1997 Medzhitov and Janeway publication. This very clearly, and indisputably, makes this publication an independent and seminal piece of work.

You either couldn’t be bothered to read the crucial bit of literature, which is pretty bad, or decided willfully to misrepresent it, which is worse. Consequently, you’ll understand that I can’t attach too much importance to the rest of your argument (rant might be a better word) either.

@ Ephraim – I think the evolution of pattern recognition is definitely interesting, but not necessarily as important in terms of its impact on medicine.

@ Viktor – Since I am writing a blog meant to appeal to people without a science background, I decided not to go into the details of forward vs reverse genetics, not because I didn’t read it (I did) or because I was “willfully misrepresenting” it (I wasn’t), but because I don’t think it changes the argument one way or the other. Functionally, he showed that a mutation in TLR4 lacked LPS responsiveness. Just because the later was known first, it doesn’t actually change the point of this post.

Beulter was looking for the LPS receptor, full stop. As you say, they may have been working on it for years, but just because something is hard, that doesn’t make it better. In the commentary on the Godowsky paper 3 months before Beutler published, Craig Gerard pointed out that the C3H/HeJ mutation was known to be syntenic with human TLR4 (Gerard, C. 1998. Bacterial infection. For whom the bell tolls. Nature 395, 217–219), and based on their earlier work, Medzhitov and Janeway were in the process of sequencing the TLR4 locus for exactly this reason when Beutler published his Science paper.

And again, that TLR4 is a receptor for a microbial product is not all that interesting. There are many receptors for many microbial products, and several were known long before TLR4. The importance of TLR’s comes from their ability to activate co-stimulation and instruct the adaptive immune system. Again, Beutler did not provide any of that insight, or even mention this fact in his Science paper.

So no, I can’t understand why you disregard (or at least fail to address) any of the substance of my rant based on this single point.

Bruce and Jules clearly deserve the Nobel Prize. Jules showed that Toll functioned in the defense response and Bruce isolated TLR4 and showed that it was the LPS receptor. This work is expected to facilitate new drugs to combat inflammations and autoimmune disease. This translation of basic work to applied is a requirement for the Noble prize I believe.

Although one can argue that Janeway should have shared in the prize for his intellectual contribitions, the Janeway and Medzhitov paper simply isolated a putative human TLR ortholog but did not demonstrate in vivo function.

And speaking of sharing prizes, what about us plant biologists? No offense, but the discoveries of plant receptors for microbial molecules preceded the Nobel prize work by several years (see the series of papers from different labs: RPS2,N and CF9 in 1994 and Xa21 in 1995). These discoveries do not detract from the well-deserved Beutler and Hoffman awards but if we are going to quibble, might as well get the history straight.

@ Pam – I don’t think the Medzhitov/Janeway hToll paper in and of itself would be deserving of the prize, but I think the context of that paper and the many others that the two of them published around the same time is what pushes them over the edge. This is sort of the same reason I don’t think Beutler deserves it – his one paper alone isn’t a huge leap, AND he doesn’t have the intellectual contribution to point to.

That said, I absolutely agree that plant folks get short shrift. As evidence – For a long time, I thought that TIR domain (the protein-protein interaction domain of TLR’s and their adaptors) stood for “Toll/IL-1 Receptor” domain. Turns out the “R” is for “resistance,” which is for the plant resistance protein that has the same domain.

hi kevin
Actually the plant people did use TIR to mean Toll/IL-1 Receptor. This is because the TOLL Protein and ILR-1 had already been cloned and characterized. However this was in 1994 before Hofffman’s discovery. The NBS-TIR class of resistance genes are not analagous to TLR4 because they do not recognize conserved microbial signatures. In plants, rice XA21, Arabidopsis FLS2 and EFR can be considered TLR4 orthologs because they bind PAMP ligands. XA21 was isolated using positional cloning in 1995. For more info, please see the review that Bruce Beutler and I wrote in Science last year. You can download it from my post on the Nobel prize.

Thank you for the article Kevin, and also thanks to everyone who posted comments for a lively and educational discussion. I absolutely agree Medzhitov deserved the Nobel- to leave him out does a disservice to Janeway’s memory and flies in the face of the (more appropriate) choice of the Shaw prize triad (Hoffman-Beutler-Medzhitov).

Cenk Sumen’s comment comes late but is certainly not without serious merit. For those who question the contribution of some of the individuals involved it is worthwhile reading the Essay written for the Shaw Prize because it very clearly documents the contribution of each. Of course giving the Nobel to Hoffman, Beutler and Medzhitov would relegate Ralph Steinman’s discovery of dendritic cells to history. Would that be fair? I don’t think so.

I am not impressed that either Medzditov or Beutler deserved a Nobel prize. But my opinion is of little importance.

Let’s consider the following: did Steinman REALLY deserve the Nobel prize because he discovered the DC? I am not trying to speak badly of the dead, but I would like to know by what criteria this is Nobel prize work. For example, whatever happened to the guy who discovered the B cell? Did he get a Nobel Prize (answer: no).

The truth is that the Nobel committee has to pick someone every year. They can never pick God, so the rest of the awardees will always be viewed as undeserving by someone.

Your comments are spot on and this was an obvious mistake by the Nobel committee. The recent letter from the top immunologists in Nature, commentary in Lancet, and the NY Times interview just published all support the views of those who really followed how the pattern recognition receptor story. Great blog post.

while searching for Janeway’s seminal work “Approaching the Asymptote? Evolution and revolution in immunology” i found your blog. great post. do u still have a copy of it? i would greatly appreciate a copy (i wrote this in comment part since the “email” link you gave above gives a ‘not found’ page). thx in advance.
my email: [removed by Kevin]

So, where is Shizuo Akira in this whole story? In Japan, he was somewhat regarded as a candidate for the Nobel price, but now that Beutler, Hoffmann, and Steinman got the price for very closely related work, his chances seem to be close to 0. His name does not appear in this blog post, nor in the discussion following it. I am not an expert in the field, so it’s hard for me to judge, but why is he not considered?

Akira doesn’t show up in this narrative because he came a bit late to the party, though once he arrived, he made a number of substantial discoveries. He was the first to knock out (and determine the roles of) many of the key components in the TLR signaling pathway like MyD88, and he discovered many other TLRs and determined their ligands. It would be impossible to overstate Akira’s contributions to the TLR field, but as the Nobels were given for the initial discoveries that launched the field, it wouldn’t make sense to include him.